1. Field of the Invention
The present invention relates in general to the preparation of porous biodegradable polymers, and in particular to a method for making crosslinked porous biodegradable polymers.
2. Description of the Related Arts
Porous biodegradable polymers are useful in a variety of pharmaceutical applications, such as physiological repair and reconstruction, for surgical sutures and internal bone fixation, for burn wound coverings, and for drug delivery systems. The biodegradable polymer itself, as it disintegrates in vivo, will be gradually replaced by the new tissue. The time required for the degradation of the biodegradable polymer is related to the degree of crosslinking. The biological degradation takes place at a slower rate as the degree of crosslinking increases. By varying the degree of crosslinking it is possible to adjust the biological degradation rate in a targeted manner for wound closure, vascular grafts, surgical meshes, surgical implants, composite bone plates, drug control release devices or tissue engineering.
Several techniques have been used to fabricate polymers into porous matrices, including freeze-drying, critical point drying, and air drying. The porous polymer thus obtained is subjected to crosslinking to increase the mechanical properties and the degradation time. The crosslinking techniques for biodegradable polymers can be divided into two categories, physical techniques and chemical techniques. The physical techniques include the thermo-dehydration and UV or xcex3-ray radiation, which have found limited use due to non-uniform or insufficient crosslinking.
The chemical techniques include liquid phase crosslinking and gas phase crosslinking. In liquid phase crosslinking, the polymer is immersed in a solution of a crosslinking agent over a specified period of time. The crosslinked polymer is recovered, washed with solvent to remove any unreacted crosslinking agent, and then freeze-dried. In vapor phase crosslinking, the polymer is placed above the solution of a crosslinking agent, and the reaction is performed under the vapor of the crosslinking agent by heating the solution. The crosslinked polymer is flushed with air flow to remove unreacted crosslinking agent.
One important drawback of the liquid phase crosslinking is that the pore structure often changes or even collapses during freeze-drying, thus increasing the difficulty of controlling the pore morphology. As to the vapor phase crosslinking, the degrees of crosslinking are not uniform over the polymer matrix, and more worse, the crosslinking agent often remains in the polymer after processing. Residue of crosslinking agent may damage transplanted cells and nearby tissue and deactivate many biologically active factors that one might wish to incorporate into the polymer matrix. For example, glutaraldehyde, the most commonly used crosslinking agent, has been found to be cytotoxic and may cause local tissue calcification.
From the above, it is apparent that an improved method for crosslinking porous biodegradable polymers which can eliminate the problems of the conventional techniques is highly desirable.
A first object of the invention to provide a method for crosslinking porous biodegradable polymers that substantially obviates the above-mentioned problems.
A second object of the invention is to provide a method for crosslinking porous biodegradable polymers, by which the destruction of pore structures can be avoided.
A third object of the invention is to provide a method for crosslinking porous biodegradable polymers, by which the polymer matrix is uniformly crosslinked.
A fourth object of the invention is to provide a method for crosslinking porous biodegradable polymers that assures complete removal of any unreacted crosslinking agents.
A fifth object of the invention is to provide a method for crosslinking porous biodegradable polymers which can use any crosslinking agent without regard to its vapor pressure.
A sixth object of the invention is to provide a method of crosslinking porous biodegradable polymers which is relatively simple, rapid, and easily tailorable.
To achieve the above objects, the present invention is characterized by the use of supercritical fluids to proceed crosslinking of polymers, and subsequently remove unreacted crosslinking agent. The method according to the invention comprises the steps of: (a) placing a porous biodegradable polymer in a chamber; (b) introducing a supercritical fluid containing a crosslinking agent into the chamber to effect crosslinking of the porous biodegradable polymer; and optionally (c) introducing a pure supercritical into the chamber to wash the crosslinked polymer until the crosslinking agent is substantially removed from the polymer.
By this method, the problems of insufficient or non-uniform crosslinking and incomplete removal of crosslinking agent are eliminated. Additionally, this method is simple, rapid and results in no structural changes of the pore structure. Furthermore, different degrees of crosslinking can be regulated by the operating parameters.